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Additionally, PCSK9 has been suggested to participate in immunoregulation by modulating cytokine production. We studied the immunological role of PCSK9 in <jats:italic>Streptococcus pneumoniae<\/jats:italic> bacteraemia in vivo and in a human hepatocyte cell line.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>CRISPR\/Cas9 mutagenesis was utilized to create <jats:italic>pcsk9<\/jats:italic> knock\u2010out (KO) zebrafish, which were infected with <jats:italic>S pneumoniae<\/jats:italic> to assess the role of PCSK9 for the survival of the fish and in the transcriptomic response of the liver. The direct effects of PCSK9 on the expression of acute\u2010phase reaction (APR) genes were studied in HepG2 cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The <jats:italic>pcsk9<\/jats:italic> KO zebrafish lines (<jats:italic>pcsk9<\/jats:italic><jats:sup>tpu\u201013<\/jats:sup> and <jats:italic>pcsk9<\/jats:italic><jats:sup>tpu\u20102,+15<\/jats:sup>) did not show developmental defects or gross phenotypical differences. In the <jats:italic>S pneumoniae<\/jats:italic> infected zebrafish, the mortality of <jats:italic>pcsk9<\/jats:italic> KOs was similar to the controls. A liver\u2010specific gene expression analysis revealed that a pneumococcal challenge upregulated <jats:italic>pcsk9<\/jats:italic>, and that the <jats:italic>pcsk9<\/jats:italic> deletion reduced the expression of APR genes, including <jats:italic>hepcidin antimicrobial peptid<\/jats:italic>e (<jats:italic>hamp<\/jats:italic>) and <jats:italic>complement component 7b<\/jats:italic> (<jats:italic>c7b<\/jats:italic>). Accordingly, silencing <jats:italic>PCSK9<\/jats:italic> in vitro in HepG2 cells using small interfering RNAs (siRNAs) decreased <jats:italic>HAMP<\/jats:italic> expression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>We demonstrate that PCSK9 is not critical for zebrafish survival in a systemic pneumococcal infection. However, <jats:italic>PCSK9<\/jats:italic> deficiency was associated with the lower expression of APR genes in zebrafish and altered the expression of innate immunity genes in a human hepatocyte cell line. Overall, our data suggest an evolutionarily conserved function for PCSK9 in APR in the liver.<\/jats:p><\/jats:sec>","DOI":"10.1111\/liv.14993","type":"journal-article","created":{"date-parts":[[2021,6,26]],"date-time":"2021-06-26T16:56:38Z","timestamp":1624726598000},"page":"2511-2522","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Proprotein convertase subtilisin\/kexin type 9 regulates the production of acute\u2010phase reactants from the liver"],"prefix":"10.1111","volume":"41","author":[{"given":"Dafne","family":"Jacome Sanz","sequence":"first","affiliation":[{"name":"Laboratory of Immunoregulation Faculty of Medicine and Health Technology Tampere University Tampere Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anni K.","family":"Saralahti","sequence":"additional","affiliation":[{"name":"Laboratory of Experimental Immunology Faculty of Medicine and Health Technology Tampere University Tampere Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meeri","family":"Pekkarinen","sequence":"additional","affiliation":[{"name":"Laboratory of Computational Biology Faculty of Medicine and Health Technology Tampere University Tampere Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juha","family":"Kesseli","sequence":"additional","affiliation":[{"name":"Laboratory of Computational Biology Faculty of Medicine and Health Technology Tampere University Tampere Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matti","family":"Nykter","sequence":"additional","affiliation":[{"name":"Laboratory of Computational Biology Faculty of Medicine and Health Technology Tampere University Tampere Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mika","family":"R\u00e4met","sequence":"additional","affiliation":[{"name":"Laboratory of Experimental Immunology Faculty of Medicine and Health Technology Tampere University Tampere Finland"},{"name":"Vaccine Research Center Faculty of Medicine and Health Technology Tampere University Tampere Finland"},{"name":"PEDEGO Research Unit Medical Research Center University of Oulu Oulu Finland"},{"name":"Department of Children and Adolescents Oulu University Hospital Oulu Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6623-844X","authenticated-orcid":false,"given":"Markus J. 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